Various publications or patents are referred to throughout this application or at the end of this specification to describe the state of the art to which the invention pertains. Each of these publications or patents is incorporated by reference herein. Complete citations of scientific publications are set forth at the end of the specification.
An individual's reproductive choices are among the most serious and personal choices made in a lifetime. It is important to be able to control fertility so that an individual is able to conceive when desired, but also to prevent pregnancy at all other times. Both infertility and unwanted pregnancy can have grave economic, emotional, and psychological impacts.
Infertility affects about 5.3 million people in the United States alone and is a disease of the reproductive system that impairs the body's ability to perform the basic function of reproduction. Infertility, defined as the inability to conceive after one year of unprotected intercourse, can be attributed to the male, the female, or sometimes both parties. Women tend to be most fertile in their early 20s and fertility declines rather slowly until about age 35, after which it declines rapidly. If women turn to in vitro fertilization (IVF) to aid the conception process, the treatment is expensive and only has about a 30% success rate with the current state of the art. Contraception is another key reproductive choice that is the foundation of a multibillion dollar industry. Any improvement in the arts of treatment of infertility and providing contraception would be significant.
When focusing particularly on the female role in reproduction, one key factor in female fertility is the oocyte itself. The process of oocyte maturation and follicle development is a complex and carefully orchestrated phenomenon, involving gonadotropin hormones and a rapidly expanding list of other intraovarian regulators. (Giudice, et al. (1996)). These regulators include growth factors belonging to the insulin-like growth factor family and the transforming growth factor-beta family. Examples of other known intraovarian regulators include cytokines and factors influencing angiogenesis, such as vascular endothelial growth factor.
Neurotrophins are a family of soluble polypeptide growth factors widely recognized for their roles in the mammalian nervous system. They include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4/5 (NT-4/5) and neurotrophin-3 (NT-3). Although originally described in the nervous system, many members of the neurotrophin family are expressed in a variety of non-neuronal tissues including the cardiovascular, immune, endocrine and reproductive systems. (Tessarollo (1998) and Yamamoto, et. al (1996)). Several members of the neurotrophin family (NGF, BDNF, NT-4/5, NT-3) and their respective receptor tissue tyrosine kinases (Trk A for NGF, Trk B for BDNF and NT-4/5 and Trk C for NT-3) have been found to be expressed in the mammalian ovary. (Dissen, et. al (1996)). Researchers initially thought the action of neurotrophins within the rodent ovary was limited to their support of ovarian innervation. However, in recent years some of these neurotrophins and their respective receptors have been found to influence rodent ovarian function including ovulation (Mayerhoffer, et. al (1996)), steroid secretion (Waraksa, et. al (1995)) and follicular development (Lara, et. al (1990) Endocrinology. 126: 357-363 and 364-375, Dissen et. al (1995), and Ojeda, et. al (2000)). In the testis, neurotrophins and their receptors have been clearly associated with spermatogenesis, demonstrating distinct distributions between somatic and germ cells. (Vesa, et al. (2000) and Seidl, et al. (1996)). Nerve growth factor activation of Trk A in cultured thecal cells is involved in disruption of gap junctions (Mayerhoffer, et al. (1996)) and may stimulate cyclooxygenase II production, progesterone secretion and cell proliferation (Parvinen, et al. (1992)), events associated with ovulation. Until now, there has been no description in the art of using neurotrophins to manipulate the reproductive capacity of female subjects. With the impact for both individuals making personal reproductive choices, the doctors who treat the individuals, and the drug companies that manufacture pharmaceuticals, it would be a significant improvement in the art if neurotrophins could be utilized to manipulate fertility and as a diagnostic for reproductive capacity in female subjects. Any invention that can decrease the cost and reduce the emotional strain related to controlling fertility would be highly useful in the art.